Androgel
FDA Label NDC 17139-501

• Virilization has been reported in children who were secondarily exposed to testosterone gel [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].
  
• Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
  
• Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Patient Counseling Information (17)].

AndroGel 1% is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

• Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
  
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations, but have gonadotropins in the normal or low range.

Limitations of use:

• Safety and efficacy of AndroGel 1% in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
  
• Safety and efficacy of AndroGel 1% in males less than 18 years old have not been established [see Use in Specific Populations (8.4)].
  
• Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure (1, 12.3).

Dosage and Administration for AndroGel 1% differs from AndroGel 1.62%. For dosage and administration of AndroGel 1.62% refer to its full prescribing information. (2)

Prior to initiating AndroGel 1%, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.

The recommended starting dose of AndroGel 1% is 50 mg of testosterone (4 pump actuations, two 25 mg packets or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day).

Dose Adjustment

To ensure proper dosing, serum testosterone concentrations should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily AndroGel 1% dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician. If the serum testosterone concentration exceeds the normal range, the daily AndroGel 1% dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 50 mg, AndroGel 1% therapy should be discontinued. In addition, serum testosterone concentrations should be assessed periodically.

The application site and dose of AndroGel 1% are not substitutable with other topical testosterone products.

AndroGel 1% should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient’s short sleeve T-shirt. Do not apply AndroGel 1% to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. AndroGel 1% should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen.

The prescribed daily dose of AndroGel 1% should be applied to the right and left upper arms/shoulders and/or right/left abdomen as shown in the shaded areas in the figures below.

Front View (Androgel 1 Front View)

Side View (Androgel 1 Side View)

After applying the gel, the application site should be allowed to dry prior to dressing. Hands should be washed thoroughly with soap and water after application. Avoid fire, flames or smoking until the gel has dried since alcohol-based products, including AndroGel 1%, are flammable.

The patient should be advised to avoid swimming or showering for at least 5 hours after the application of AndroGel 1%.

Multi-Dose Pump

To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, patients should completely depress the pump one time actuation for every 12.5 mg of testosterone required to achieve the daily prescribed dosage. The product should be delivered directly into the palm of the hand and then applied to the desired application sites. Alternatively, AndroGel 1% can be applied directly to the application sites. Table 1 provides dosing information for adult males.

Packets

The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AndroGel 1%-treated skin:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1%.
• Patients should wash hands with soap and water immediately after application of AndroGel 1%.
• Patients should cover the application site(s) with clothing (e.g., a T-shirt) after the gel has dried.
• Prior to situation in which direct skin-to-skin contact is anticipated, patients should wash the application site thoroughly with soap and water to remove any testosterone residue.
• In the event that unwashed or unclothed skin to which AndroGel 1% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible.

AndroGel (testosterone gel) 1% for topical use only, is available as follows:

• A metered-dose pump. Each pump actuation delivers 12.5 mg of testosterone in 1.25g of gel.
• A unit dose packet containing 25 mg of testosterone provided in 2.5 g of gel.
• A unit dose packet containing 50 mg of testosterone provided in 5 g of gel.

• AndroGel 1% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.4), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)].
• AndroGel 1% is contraindicated in women who are pregnant. AndroGel 1% can cause virilization of the female fetus when administered to a pregnant woman. Pregnant women need to be aware of the potential for transfer of testosterone from men treated with AndroGel 1%. If a pregnant woman is exposed to AndroGel 1%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using AndroGel 1% [see Dosage and Administration (2.2), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.

Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events.

There have been postmarketing reports of venous thromboembolic events (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as AndroGel 1%.

In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, AndroGel 1% was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) [see Adverse Reactions (6.1)].

Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with AndroGel 1% and initiate appropriate workup and management [see Adverse Reactions (6.2)].

• Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.
• Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications (4), Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)].

AndroGel 1% can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, AndroGel 1.62% increased the mean systolic/diastolic blood pressure by 1.9/1.3 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, AndroGel 1.62% increased the mean systolic/diastolic BP by 3.0/2.2 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time.

The CV risk associated with AndroGel 1.62% was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, mean systolic blood pressure in the group treated with AndroGel 1.62% was increased by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for AndroGel 1.62% vs 7.3% for placebo) [See Adverse Reactions (6.1)].

Monitor blood pressure periodically in men using AndroGel 1.62%, especially men with hypertension. AndroGel 1.62% is not recommended for use in patients with uncontrolled hypertension.

Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions [see Drug Abuse and Dependence (9)].

If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

Due to the lack of controlled evaluations in women and potential virilizing effects, AndroGel 1% is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.2)].

With large doses of exogenous androgens, including AndroGel 1%, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. AndroGel 1% is not known to cause these adverse effects.

Androgens, including AndroGel 1%, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse Reactions (6.2)].

Gynecomastia may develop and persist in patients being treated with androgens, including AndroGel 1%, for hypogonadism.

The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases [see Adverse Reactions (6.2)].

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as AndroGel 1%. Monitor the lipid profile periodically, particularly after starting testosterone therapy.

Androgens, including AndroGel 1%, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

Androgens, including AndroGel 1%, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Alcohol based products, including AndroGel 1%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the AndroGel 1% has dried.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials in Hypogonadal Men

Table 2 shows the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel 1% and reported by >1% of patients in a 180 Day, Phase 3 study.

Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.

In this 180-day clinical trial, skin reactions at the site of application were reported with AndroGel 1%, but none was severe enough to require treatment or discontinuation of drug.

Six patients (4%) in this trial had adverse events that led to discontinuation of AndroGel 1%. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to AndroGel 1% administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No AndroGel 1% patient discontinued due to skin reactions.

In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel 1%; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other.

In a 3-year, flexible dose, extension study, the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel 1% and reported by > 1% of patients is shown in Table 3.

Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP).

Discontinuation for adverse events in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient).

Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men

During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on AndroGel 1% in the 3-year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL.

Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as >2X the baseline or any single serum PSA >6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still <2 ng/mL. The first occurrence of a pre-specified, post- baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%).

Four patients met this criterion by having a serum PSA >6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient’s PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient’s PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.

Blood Pressure Increases

In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 246 patients. ABPM was conducted at baseline and at Week 16 of AndroGel 1.62% therapy. A total of 169 patients had acceptable ABPM recordings at both baseline and Week 16 and also were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic blood pressure (BP) and diastolic BP from baseline to end-of-treatment at Week 16 (n=169) was 1.9 mm Hg (95% CI 0.6, 3.1) and 1.3 mm Hg (95% CI 0.5, 2.1), respectively. In patients with a history of hypertension who were being treated with antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 3.0 mm Hg [95% CI 0.8, 5.2] and 2.2 mm Hg [95% CI 0.8, 3.5], respectively [n=72]). In patients with no history of hypertension at baseline, the mean systolic and diastolic blood pressure increased by 1.2 mm Hg [95% CI -0.2, 2.7] and 0.9 mm Hg [95% CI -0.1, 1.8], respectively [n=91]).

Four patients (2.8%) on AndroGel 1.62%, all of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive regimen adjusted during the ABPM study.

Of the 246 patients who used AndroGel during the study, 10 patients (4.1%) were reported to have either an adverse reaction of hypertension (5 patients, 2.0%) or increased blood pressure (5 patients, 2.0%).

Cardiovascular Outcomes

TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the CV safety of AndroGel 1.62% compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued AndroGel 1.62% or placebo therapy. The mean (±SD) daily dose of testosterone was 65±22 mg.

The mean patient age (±SD) was 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35kg/m2. Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively.

The mean serum testosterone concentration at baseline in patients receiving AndroGel 1.62% was 220.4 ng/dL (n= 2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving AndroGel 1.62% were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively.

For patients treated with AndroGel 1.62%, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of AndroGel 1.62% versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]).

Additional Adverse Reactions Reported in TRAVERSE

Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in AndroGel 1.62% versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.

The following adverse reactions have been identified during post approval use of AndroGel 1%. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (Table 4).

Secondary Exposure to Testosterone in Children

Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarket surveillance. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary exposure from items such as the testosterone gel user's shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions (5.1)].

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease insulin requirements.

Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

The concurrent use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.

Risk Summary

AndroGel 1% is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action [see Contraindications (4) and Clinical Pharmacology (12.1)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies.

Data

Animal Data

In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased ano-genital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes.

Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

Risk Summary

AndroGel 1% is not indicated for use in women.

Infertility

Testis disorder, testicular atrophy, and oligospermia have been identified during use of AndroGel 1% [see Adverse Reactions (6.1, 6.2)].

During treatment with large doses of exogenous androgens, including AndroGel 1%, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions (5.8)]. Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence (9.2)]. With either type of use, the impact on fertility may be irreversible.

The safety and effectiveness of AndroGel 1% in pediatric patients less than 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AndroGel 1% to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer.

Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH.

No studies were conducted involving patients with renal impairment.

No studies were conducted in patients with hepatic impairment.

AndroGel 1% contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Behaviors Associated with Addiction

Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:

• Taking greater dosages than prescribed
  
• Continued drug use despite medical and social problems due to drug use
  
• Spending significant time to obtain the drug when supplies of the drug are interrupted
  
• Giving a higher priority to drug use than other obligations
  
• Having difficulty in discontinuing the drug despite desires and attempts to do so
  
• Experiencing withdrawal symptoms upon abrupt discontinuation of use

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.

Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone concentrations of up to 11,400 ng/dL with a cerebrovascular accident.

Treatment of overdosage would consist of discontinuation of AndroGel 1%, washing the application site with soap and water, and appropriate symptomatic and supportive care.

AndroGel 1% for topical use is a clear, colorless gel containing testosterone. Testosterone is an androgen. AndroGel 1% is available in a metered-dose pump or unit dose packets.

The active pharmacologic ingredient in AndroGel 1% is testosterone, an androgen. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

Structural Formula (Androgel 1 Structural)

Pharmacologically inactive ingredients in AndroGel 1% are carbomer 980, ethanol 67.0%, isopropyl myristate, purified water, and sodium hydroxide. These ingredients are not pharmacologically active.

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement; vocal chord thickening; and alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

No specific pharmacodynamic studies were conducted using AndroGel 1%.

Absorption

AndroGel 1% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (298 - 1043 ng/dL) seen in healthy men. AndroGel 1% provides continuous topical delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

AndroGel 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from AndroGel is absorbed into systemic circulation. In a study with AndroGel 1% 100 mg, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing.

With single daily applications of AndroGel 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (less than 300 ng/dL) maintained on AndroGel 1% 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by AndroGel 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by AndroGel 1% 50 mg 566 (±262) ng/dL.

Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying AndroGel 1% Once Daily

Figure 1 (Androgel 1 Figure 1)

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT).

DHT concentrations increased in parallel with testosterone concentrations during AndroGel 1% treatment. The mean steady-state DHT/T ratio during 180 days of AndroGel treatment ranged from 0.23 to 0.29 (50 mg of AndroGel 1%/day) and from 0.27 to 0.33 (100 mg of AndroGel 1%/day).

Excretion

There is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

When AndroGel 1% treatment is discontinued after achieving steady state, serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application.

Testosterone Transfer from Male Patients to Female Partners

The potential for dermal testosterone transfer following AndroGel 1% use was evaluated in a clinical study between males dosed with AndroGel 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of testosterone administered as AndroGel 1% by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the AndroGel 1% application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration >2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.

Carcinogenesis

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenesis

Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous testosterone has been reported to suppress spermatogenesis in rats, dogs, and non-human primates, which was reversible on cessation of the treatment.

AndroGel 1% was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to AndroGel 1% 50 mg daily, 78 patients to AndroGel 1% 100 mg daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of AndroGel 1% but open-label for active control. Patients who were originally randomized to AndroGel 1% and who had single-sample serum testosterone concentrations above or below the normal range on Day 60 were titrated to 75 mg daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel 1% 50 mg daily, 52 patients continued on AndroGel 1% 100 mg daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel 1% 75 mg daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of AndroGel 1% for an additional period of up to 3 years.

Mean peak, trough and average serum testosterone concentrations within the normal range (298- 1043 ng/dL) were achieved on the first day of treatment with doses of 50 mg and 100 mg of AndroGel 1%. In patients continuing on AndroGel 1% 50 mg and 100 mg, these mean testosterone concentrations were maintained within the normal range for the 180-day duration of the original study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as AndroGel 1% for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed AndroGel 1% treatment.

Figure 2: Mean Steady-State Testosterone Concentrations in Patients with Once-Daily AndroGel 1% Therapy

Figure 2 (Androgel 1 Figure 2)

Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 50 mg, 75 mg, or 100 mg of AndroGel 1%. The 75 mg dose produced mean concentrations intermediate to those produced by 50 mg and 100 mg of AndroGel 1%.

Of 129 hypogonadal men who were appropriately titrated with AndroGel 1% and who had sufficient data for analysis, 87% achieved an average serum testosterone concentration within the normal range on Treatment Day 180.

In patients treated with AndroGel 1%, there were no observed differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypogonadism, or body mass index.

DHT concentrations increased in parallel with testosterone concentrations at AndroGel 1% doses of 50 mg/day and 100 mg/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physiologically active androgen. Serum estradiol (E2) concentrations increased significantly within 30 days of starting treatment with AndroGel 1% 50 or 100 mg/day and remained elevated throughout the treatment period but remained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during AndroGel 1% treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent manner during treatment with AndroGel 1%.

The phototoxic potential of AndroGel 1% was evaluated in a double-blind, single-dose study in 27 subjects with photosensitive skin types. The Minimal Erythema Dose (MED) of ultraviolet radiation was determined for each subject. A single 24 (+1) hour application of duplicate patches containing test articles (placebo gel, testosterone gel, or saline) was made to naive skin sites on Day 1. On Day 2, each subject received five exposure times of ultraviolet radiation, each exposure being 25% greater than the previous one. Skin evaluations were made on Days 2 to 5. Exposure of test and control article application sites to ultraviolet light did not produce increased inflammation relative to non-irradiated sites, indicating no phototoxic effect.

AndroGel 1% is supplied in non-aerosol, metered-dose pumps that deliver 12.5 mg of testosterone per complete pump actuation. The pumps are composed of plastic and stainless steel and an LDPE/aluminum foil inner liner encased in rigid plastic with a polypropylene cap. Each 88 g metered-dose pump is capable of dispensing 75 g of gel or 60-metered pump actuations; each pump actuation dispenses 1.25 g of gel.

AndroGel 1% is supplied in unit-dose aluminum foil packets in cartons of 30. Each packet of 2.5 g or 5 g gel contains 25 mg or 50 mg testosterone, respectively.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Disposal

Used AndroGel 1% pumps or used AndroGel 1% packets should be discarded in household trash in a manner that prevents accidental application or ingestion by children or pets.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patients should be informed of the following:

Men with known or suspected prostate or breast cancer should not use AndroGel 1% [see Contraindications (4) and Warnings and Precautions (5.4)].

Secondary exposure to testosterone in children and women can occur with the use of testosterone gel in men [see Warnings and Precautions (5.1)]. Cases of secondary exposure to testosterone have been reported in children.

Physicians should advise patients of the reported signs and symptoms of secondary exposure, which may include the following:

• In children: unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior
  
• In women: changes in hair distribution, increase in acne, or other signs of testosterone effects
  
• The possibility of secondary exposure to testosterone gel should be brought to the attention of a healthcare provider
  
• AndroGel 1% should be promptly discontinued until the cause of virilization is identified

Strict adherence to the following precautions is advised to minimize the potential for secondary exposure to testosterone from testosterone gel in men [see Medication Guide]:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel
  
• Patients using AndroGel 1% should apply the product as directed and strictly adhere to the following:
  ○ Wash hands with soap and water immediately after application
  ○ Cover the application site(s) with clothing after the gel has dried
  ○ Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated
  ○ In the event that unwashed or unclothed skin to which AndroGel 1% has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Inform patients that AndroGel 1% can cause venous thromboembolism. Advise patients of the signs and symptoms of venous thromboembolism, which may include the following: lower limb pain, edema, or erythema; and dyspnea or chest pain. Advise patients to promptly report the signs and symptoms of venous thromboembolism, discontinue use of AndroGel 1%, and seek urgent medical care.

Inform patients that AndroGel 1% can increase BP which can increase cardiovascular risk over time. Instruct patients about the importance of monitoring BP periodically while on Androgel 1%. If BP increases while on AndroGel 1%, antihypertensive medications may need to be started, added, or adjusted to control BP, or AndroGel 1% may need to be discontinued.

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

• Changes in urinary habits such as increased urination at night, trouble starting your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having a urine accident, being unable to pass urine and weak urine flow.
• Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness.
• Too frequent or persistent erections of the penis.
• Nausea, vomiting, changes in skin color, or ankle swelling.

• Read the Medication Guide before starting AndroGel 1% therapy and to reread it each time the prescription is renewed
• AndroGel 1% should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women
• Keep AndroGel 1% out of the reach of children
• AndroGel 1% is an alcohol based product and is flammable; therefore avoid fire, flame or smoking until the gel has dried
• It is important to adhere to all recommended monitoring
• Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood
• AndroGel 1% is prescribed to meet the patient's specific needs; therefore, the patient should never share AndroGel 1% with anyone.
• Wait 5 hours before swimming or washing following application of AndroGel 1%. This will ensure that the greatest amount of AndroGel 1% is absorbed into their system.

Marketed by:

ASCEND Therapeutics US, LLC Bridgewater, NJ08807, USA

© 2025 ASCEND Therapeutics US, LLC

2025AG0002 Revised July, 2025

This Medication Guide has been approved by the U.S. Food and Drug Administration                  Revised: 07/2025

2025AG0002

Read this Instructions for Use for ANDROGEL 1% before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Applying ANDROGEL 1%:

• Before applying ANDROGEL 1%, make sure that your shoulders, upper arms or stomach are clean, dry, and there is no broken skin.
• The application sites for ANDROGEL 1% are the shoulders, upper arms or stomach area (abdomen) that will be covered by a short sleeve t-shirt (see Figure A). Do not apply ANDROGEL 1% to any other parts of your body such as your penis, scrotum, chest, armpits (axillae), knees, or back.


Figure A (Androgel 1 Figure A)

ANDROGEL 1% comes in a pump or in packets.

If you are using the ANDROGEL 1% pump:

• Before using a new bottle of ANDROGEL 1% for the first time, you will need to prime the pump. To prime the ANDROGEL 1% pump, slowly push the pump all the way down 3 times. Do not use any ANDROGEL 1% that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your ANDROGEL 1% pump is ready to use.
• Remove the cap from the pump. Then, position the nozzle over the palm of your hand and slowly push the pump all the way down. Apply ANDROGEL 1% to the application site. You may also apply ANDROGEL 1% directly to the application site.
• Wash your hands with soap and water right away.
• Your healthcare provider will tell you the number of times to press the pump for each dose.

If you are using the ANDROGEL 1% packets:

• Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top.
• Squeeze all of the ANDROGEL 1% out of the packet into the palm of your hand.
• Apply ANDROGEL 1% to the application site. You may also apply ANDROGEL 1% from the packet directly to the application site.
• Let the application areas dry completely before putting on a t-shirt.
• ANDROGEL 1% is flammable until dry. Let ANDROGEL 1% dry before smoking or going near an open flame.
• Wash your hands with soap and water right away after applying ANDROGEL 1%.
• Avoid showering, swimming, or bathing for at least 5 hours after you apply ANDROGEL 1%.

How should I store ANDROGEL 1%?

• Store ANDROGEL 1% at room temperature between 68°F to 77°F (20°C to 25°C).

• Safely throw away used ANDROGEL 1% in the household trash. Be careful to prevent accidental exposure of children or pets.

• Keep ANDROGEL 1% away from fire.
  
  

Keep ANDROGEL 1% and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 10/2025

2025AG0002

NDC 17139–525–30 For Topical Use Only
Contains 25 mg of testosterone
(2.5 Grams of gel)

AndroGel ^® (testosterone gel) 1% CIII

Please read Medication Guide

Rx Only

Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure.

WARNINGS: Keep out of reach of children. ALCOHOL BASED GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING UNTIL GEL HAS DRIED

Ascend Therapeutics

Ndc 17139-525-30 (17139 525 30)

NDC 17139–550–30 For Topical Use Only
Contains 50 mg of testosterone
(5 Grams of gel)

AndroGel ^® (testosterone gel) 1% CIII

Please read Medication Guide

Rx Only

Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure.

WARNINGS: Keep out of reach of children. ALCOHOL BASED GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING UNTIL GEL HAS DRIED

Ascend Therapeutics

Ndc 17139-550-30 (17139 550 30)

NDC 17139–501–02

AndroGel ^® (testosterone gel) 1% CIII

Ascend Therapeutics

Ndc 17139-501-02 (Pump Label)